Methods and apparatus for treating neurovascular venous outflow obstruction

ABSTRACT

Methods and devices are disclosed for treating neurovascular venous outflow obstructions, with or without implantation of a prosthetic valve. The valve may be carried by a support, such as a stent, which may be self-expandable or balloon expandable. Both transvascular and direct surgical access is contemplated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/589,032, filed on May 8, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/550,748, filed on Nov. 21, 2014 (now issued asU.S. Pat. No. 9,675,457), which is a continuation of U.S. patentapplication Ser. No. 13/191,296, filed on Jul. 26, 2011 (now abandoned),which claims the priority benefit of U.S. Provisional Application No.61/400,383, filed Jul. 27, 2010. The entireties of each of the foregoingapplications is hereby incorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to methods and devices for treatingneurovascular venous outflow obstructions, such as to relieve thesymptoms of multiple sclerosis or other neurological conditions.

Multiple Sclerosis (MS) is a debilitating disease for which modernmedicine has few answers. Questions remain regarding the etiology, thedisease process, and possible treatments. Since Jean Martin Charcotfirst described the clinical and pathological features of MS in 1868 ithas perplexed physicians and scientists alike. For years the disease wasdescribed clinically, but with the advent of more sophisticated toolssuch as magnetic resonance imaging (MRI), the disease process was linkedto plaques—or inflammatory lesions—in the white matter of the centralnervous system. These lesions were characterized by a breakdown of themyelin sheath that surrounds the central axon of a nerve cell. The firstclinical signs are thought to manifest years after the pathology beginsin the brain. There is also increasing evidence that the pathology ismuch more widespread than the finite number of lesions seen on MRI. Inaddition, serial MRI studies have shown that the disease process isongoing even when clinical symptoms seem to have subsided.

The pathophysiology of the disease process has been described and isbelieved to involve an autoimmune component; however, the preciseunderlying etiology remains a mystery. MS has been associated with pastEpstein Barr Virus (EBV) exposure, smoking, geography, and it isbelieved to have some genetic component. MS affects more than 350,000people in the United States. Estimates of the prevalence of the diseaseare approximately 90 cases per 100,000 people.

The symptoms of an MS attack or flare can include: paresthesias, limbweakness, paralysis, double vision, loss of vision, incontinence, andcognitive decline. There are three main clinical courses of MS:Relapsing Remitting (RR); Secondary Progressive (SP); and PrimaryProgressive (PP). RR is characterized by acute exacerbations of thedisease followed by complete remission of the symptoms with nearlycomplete recovery. Some patients with the RR course of the disease willnot completely return to their baseline level of function. SP ischaracterized by progressive deterioration of neurologic function. Mostpatients with the RR course of the disease will eventually develop SPafter several years with RR. PP is characterized by a progressiveclinical course from the onset of the disease.

In terms of the pathophysiology, MS involves the breakdown of the myelinsheath that surrounds the central axon of a nerve. There also appears tobe widespread axonal damage. In addition, though the disease had oftenbeen considered a white matter disease, there is now some evidence ofpathology in the grey matter of the brain as well. Though the geneticaspect of MS has been studied there has been no direct genetic linkidentified. Despite the complicated set of immunological changes thataffect the myelin and axons having been studied extensively for years.In addition, there is epidemiological evidence that points to somevariable incidence of MS in different parts of the world. And yet,despite all this extensive attention and study, a cure or even aneffective treatment for MS remains out of reach.

The best medicine can provide at this point for a patient is to delaythe progression of the disease. And eventually even these patients willonly have their symptoms managed to maximize their quality of life asthe disease inevitably progresses. There is a focus in these earlytreatments on the few mechanisms thought to be important in theprogression of the disease. Anti-inflammatory therapy has been used foracute attacks of the disease, which has no more than short-term benefitto shorten the duration of the attack. Immunosuppressive therapies havebeen attempted but have provided little benefit and led to substantialside effects. As understanding of the specific immunological mechanismsinvolved in the disease process improve there are more targeted agentsbeing studied.

For almost four decades neurologists have been able to modify the acuteattacks of the disease. Since the 1990's the agents addressing thenumber and severity of attacks of MS have improved, and have reduced theactivity seen on MRI. However, there remains no long-term data thatconvincingly demonstrates a reduction in the rate of eventualprogression of the disease. The various therapies used for MS have beenapplied by trial and error and changed as the theory of the diseasechanged. There is now some new evidence that venous blood flow from thebrain may play a role in MS.

The venous circulatory system flowing from the brain is complicated.Blood is drained from the brain by back propulsion of the residualarterial pressure (i.e., negative venous pressure), and antegradepostural and respiratory mechanisms. The internal jugular vein (IJV)collects the blood from the brain, face, and neck. The IJV is directlycontinuous with the sigmoid sinus in the jugular foramen at the base ofthe skull. At the origin of the IJV, the vein is somewhat dilated—thisdilatation is called the superior bulb. It runs down the side of theneck in a vertical direction, lying at first lateral to the internalcarotid artery, and then lateral to the common carotid. At the root ofthe neck the IJV unites with the subclavian vein (SV) to form theinnominate vein. A little above its termination is a second dilatationcalled the inferior bulb. At the root of the neck, the right IJV isfarther from the common carotid, and crosses the first part of thesubclavian artery, while the left IJV usually overlaps the commoncarotid artery. The left IJV is generally smaller than the right, andeach contains a pair of valves, which are about 2.5 cm above thetermination of the vessel. The external jugular (EJV) vein receives thegreater part of the blood from the exterior of the cranium and the deepparts of the face, being formed by the junction of the posteriordivision of the retromandibular vein with the posterior vein. The EJVhas two pairs of valves, the lower pair is at the intersection with theSV, and the upper in most people is about 4 cm above the clavicle. Theportion between the two valves is often dilated and is called the sinus.These valves do not prevent the regurgitation of blood or the passage ofblood from below upward. Supine posture favors cerebral venous outflowthrough the IJV veins. In the upright position, blood is redirectedthrough the vertebral veins and the azygous vein (AZ) which becomes thepredominant pathway.

There are valves in the IJV in more than 90% of patients. These valvesare frequently located in the distal portion of the IJV. Sonographydemonstrates bilateral valves in 60% of patients, with the majority ofunilateral valves are right sided. Doppler ultrasound (US) of the IJVhas demonstrated symmetrical biphasic blood flow in 57% of 148 patients,continuous flow in 29%, and monophasic flow in 13%. Scientists havehypothesized blood flow velocity normal when it is less than 1 m/s andvaries with both respiration and heart rate. Others have reported anaverage right-plus-left jugular vein flow of 740±209 ml/min. Flow was8.7% lower in female than in male subjects, but normalization of flow to100 g brain tissue failed to reveal any significant sex difference.Normal Doppler US waveforms are characterized by two physiologicalvariations: 1) cardiac pulsatility, due to the retrograde pressure wavesof right atrial contraction, is synchronized to the pulse rate andfrequently results in a biphasic signal; 2) superimposed variationsrelated to the respiratory cycle, with an increase on inspiration and adecrease on expiration.

IJV valve incompetence has been documented for many years, and ishypothesized to be associated with various disease process includingrespiratory brain syndrome and cough headaches. The IJV valve issituated just above the termination of the IJV and is the only valvebetween the heart and the brain. If the IJV valve is damaged or becomesincompetent, increase in intrapleural pressure could result in raisedintracranial pressure. Additionally, the jugular venous pulse is usedclinically to estimate right atrial pressure. A high prevalence of IJVvalve insufficiency appears to be present in patients with clinicaldiagnosis of transient global amnesia (TGA)—suggesting that venouscongestion in areas of the brain associated with memory may partiallyexplain episodes of benign TGA. IJV valve insufficiency has been foundto be present in at least 1 side in almost 80% of patients with TGA,compared with only 25% of control subjects. There was also a trendtoward a predominance of right-sided IJV valve insufficiency. Studieshave shown valvular insufficiency in nearly 80% of subjects with TGAcompared to 25% of subjects with no history of TGA.

Ever since Jean Martin Charcot first described MS, the plaques wereknown to be venocentric. Since then magnetic resonance venographs (MRVs)and postmortem studies have shown a central vein oriented along the longaxis of the inflammatory lesion. In addition, the brains and spinalcords of patients with MS contain abnormally high levels of redoxactivemetals, particularly iron, as documented by advanced MRI studies.Histologic studies have shown disposition of iron stores in CNS venouswalls in patients with MS. In the 80's it was hypothesized that MS mightbe related to cardiorespiratory blood “backjets” as the basis for theDawson's Fingers, which are lesions seen around the CNS veins near theventricle in MS patients.

A condition called Chronic Cerebrospinal Venous Insufficiency (CCSVI)has been hypothesized to be associated with MS. Researchers havedescribed CCSVI as a condition with multiple stenoses of the principalpathways of the extracranial venous drainage, such as the IJV andAzygous vein (AV). A study from 2009 looking at 65 MS patients (35 withRR; 20 with SP; and 10 with PP) and 265 controls (60 healthy-age andgender matched; 82 healthy but older than study group; 45 with otherneurological disease; 48 with other disease scheduled for venography)examined the flow in the azygous and jugular venous system. Zamboni etal., Chronic Cerebrospinal Venous Insufficiency in Patients withMultiple Sclerosis, 80 J. NEUROLOGY NEUROSURGERY & PSYCHIATRY 392(2009). The study focused on detection of five parameters, which aresaid to be absent in normal subjects: 1) reflux in the IJV and/orvertebral veins (VVs) in sitting and supine posture; 2) reflux in thedeep cerebral veins (DCVs); 3) high-resolution B-mode evidence of IJVstenoses; 4) flow not Doppler-detectable in the IJV and/or VVs; and 5)reverted postural control of the main cerebral venous outflow pathways.All patients with at least 2 of these criteria were reported to have“multiple significant extra-cranial stenoses” by venography. Of thepatients with these extra-cranial stenoses, 91% had IJV stenoses and 86%had AV stenosis. Of the five criteria above the study reported astatistically significant difference between patients with MS and thosewithout in each of the criteria to a P<0.001 level of significance.

Notwithstanding the foregoing, there remains a need for methods anddevices for treating neurovascular venous outflow obstructions, such asto relieve the symptoms of Multiple Sclerosis or other neurologicalconditions or disease.

SUMMARY OF THE INVENTION

There is provided in accordance with the present invention methods anddevices for treating cerebrospinal venous insufficiency, which treatmentmay reduce or eliminate certain symptoms of multiple sclerosis or otherneurological conditions. In accordance with the methods of the presentinvention, a patient is identified having at least a partial obstructionat a site in the venous outflow track from the brain. Patency isrestored by at least partially removing the obstruction, and a valve isimplanted in fluid communication with the site, to permit venous outflowand reduce retrograde pressure. The valve may be implanted at the site,or in upstream or downstream fluid communication with the site.

The removing the obstruction step may comprise inflating a dilatationballoon at the site. The dilatation balloon may additionally carry animplant at the time of the inflating step to remove the obstruction.Alternatively, following removal of the obstruction, a deploymentballoon may be positioned at the site carrying an implant for balloondeployment. The deployment balloon may be carried by a catheter, whichis introduced into the vasculature at an access point spaced apart fromthe site.

The removing the obstruction step may comprise surgically removing asection of vein. The implanting step may comprise surgically attaching avalve, or a graft containing a valve, at the site.

The method may comprise attaching a first end of a graft at a firstanastomosis to a vein and attaching a second end of the graft at asecond anastomosis to a vein. The first anastomosis may be to the rightinternal jugular, the left internal jugular or the azygos vein. Thesecond anastomosis may be to the right internal jugular, the leftinternal jugular, the right innominate, the left innominate the azygosor the superior vena cava.

Alternatively, a valve may be implanted in one or more of the leftinternal jugular, the right internal jugular, the azygos and thesuperior vena cava.

Further features and advantages of the present invention will becomeapparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follows, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of the venous outflow vasculature leadingfrom the brain.

FIG. 2 is a schematic side elevational view of a deployment catheter inaccordance with one aspect of the present invention.

FIG. 3 is a detailed view of the distal end of the catheter illustratedin FIG. 2, with an outer sheath in a proximal, retracted configuration.

FIG. 4 is a cross-sectional view taken along the lines 4-4 in FIG. 3.

FIG. 5A is a side elevational view of a flow directed valve positionedwithin a vein, in a closed configuration.

FIG. 5B is a side elevational view as in FIG. 5A, with the valve in anopen position.

FIG. 6A is a side elevational view of an alternate valve shown in aclosed position.

FIG. 6B is a side elevational view of the valve of FIG. 6A, shown in anopen position.

FIG. 7A is a side elevational view of a frame for an alternate valveconfiguration.

FIG. 7B is a top plan view of the frame shown in FIG. 7A.

FIG. 7C is a side elevational view of the frame as in FIG. 7A, togetherwith an occluder and shown in a closed configuration.

FIG. 7D is a side elevational view as in FIG. 7C, with the occluder inan open position.

FIG. 7E is top plan view of an occluder useful in the frame in FIG. 7A.

FIGS. 8A and 8B are side elevational views of stents having a bi-leafletor duckbill valve therein.

FIG. 9A is a side elevational view of a valve carried by a helical coilsupport structure.

FIG. 9B is a side elevational view of a valve having upstream anddownstream pigtail anchors.

FIG. 9C is a side elevational view of a valve coupled directly to thevessel wall with tissue penetrating anchors.

FIG. 10A is a side elevational view of a valve carried by a stent whichis provided with a plurality of tissue barbs.

FIG. 10B is a side elevational view of an implant which straddles thenative valve.

FIG. 10C is a schematic view of a valve support positioned within theleft internal jugular, and supported by the opposing wall of thesubclavian vein.

FIG. 10D is a schematic view of a valve supported by an extra vascularboney structure.

FIG. 10E is a schematic view of a valve supported by an extra vascularcuff.

FIG. 11 is a schematic view of a valve positioned within the superiorvena cava.

FIG. 12 is a schematic view of an embolic filter positioned within thesuperior vena cava.

FIG. 13 is a schematic view of a valved extravascular graft shownattached via anastomosis to the left internal jugular and the leftinnominate veins.

FIG. 14 is a schematic view of a valved graft implanted to replace asection of the left internal jugular.

FIG. 15A is a schematic plan view of a three-leaflet valve, having afabric covered annulus for surgical attachment to a vein.

FIG. 15B is a side elevational schematic view of the valve of FIG. 15A.

FIG. 16 is a side elevational schematic view of a valved graft forsurgical implantation.

FIG. 17A is a top plan view of a vein having a flap formed therein.

FIG. 17B is a cross-sectional elevational view of the section of veinshown in FIG. 17A, with the flap in an occlusive orientation.

FIG. 18A is a top plan view of a backstop for limiting movement of thetissue flap.

FIG. 18B is a side elevational view of the backstop illustrated in FIG.18A.

FIG. 19A is a side elevational schematic view of a formed in situ valve,in a closed configuration.

FIG. 19B is a side elevational view of the valve of FIG. 19A, in an openconfiguration.

FIGS. 20A-20C are side elevational schematic views of dilatationcatheters in accordance with the present invention.

FIG. 21A-21D are side elevational views of components of an alternatedilatation catheter, in which the working length of a central balloon isadjustable by axially advancing or retracting a proximal balloon carriedconcentrically over the shaft for at least one distal balloon.

FIG. 22 illustrates the catheter placed across a stenosis.

FIG. 23 illustrates the catheter of FIG. 22, with a distal ballooninflated within the vein.

FIG. 24 is an illustration as in FIG. 23, with both a distal balloon anda proximal balloon inflated on opposing sides of a stenosis in a vein.

FIG. 25 is an illustration as in FIG. 24, with a central balloonexpanded to dilate the stenosis.

FIG. 26 illustrates a balloon expandable stent, carried by a balloon andexpanded at a treatment site.

FIG. 27 illustrates the stent placed as shown in FIG. 26, with thedilatation balloon removed.

FIGS. 28A, 28C and 28D illustrate the relative dimensions of aconventional stent strut.

FIGS. 28B, 28E and 28F illustrate relative stent strut dimensions whichenable the radially outwardly inclined apex shown in FIG. 28F.

FIG. 29 is a plan view of a portion of a stent wall pattern inaccordance with the present invention.

FIG. 30 illustrates a stent positioned across a treatment site, andhaving tissue engaging barbs to resist migration.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring to FIG. 1, there is illustrated a simplified schematic of thevenous outflow vasculature leading from the brain. As illustratedtherein, venous flow from the vein is conducted via the right internaljugular vein 10 which merges with the subclavian vein 12 to form theright innominate 14, leading to the superior vena cava 16. The azygosvein 18 also leads to the superior vena cava 16.

Venous flow through the left internal jugular 20 and external jugular 22merge with the subclavian vein 24, and lead via the left innominate 26to the superior vena cava 16.

The extracranial venous vasculature described above is typically alsocharacterized by the presence of a number of valves. Althoughpatient-to-patient variation is observed, a typical patient may have afirst valve 28 and a second valve 30 within the right internal jugular10. The left internal jugular 20 may also be provided with a first valve32 and a second valve 34. In addition, the azygos vein 18 is often foundwith at least one valve 36.

In a healthy patient, the valves function to permit outflow from thecerebral vasculature, while inhibiting retrograde flow and/or pressurethroughout the cardiac cycle.

Anomalies in the venous outflow track from the brain have beenassociated with a variety of neurological conditions. For example,malformed or deformed valves can lead to regurgitant flow. Venousstenosis, which may result from either the formation of thrombus orplaque, or from extreme twisting or bending of the vein, can produceresistance to normal venous drainage. Stenotic legions in the venousvasculature are often observed in the vicinity of or involving one ormore valves, or may be spaced apart from the valves.

In accordance with the present invention, one or more therapeuticprocedures which may involve an implant are accomplished on theextracranial venous vasculature, to alleviate an abnormality in venousblood flow. As is discussed in greater detail below, the procedure maybe accomplished either via a direct surgical incision, ortransvascularly using one or more catheters introduced into the venoussystem at a remote site. The procedure may involve restoring patency tothe venous lumen, such as by balloon dilatation or other recanalizationtechnique. The procedure may additionally involve deployment of apermanent or temporary implant, such as a tubular scaffold to inhibitrestenosis of the venous lumen. One or more valves may also be deployed,and oriented to permit venous outflow but resist regurgitant pressureand/or flow. Various aspects of the invention will be described inadditional detail below.

Referring to FIG. 2, there is disclosed a catheter 40 in accordance withone aspect of the present invention. Although primarily described in thecontext of a deployment catheter having a retractable outer sheath torelease a self expanding implant, catheters of the present invention canreadily be modified to incorporate a variety of additional structuresand functionalities, such as permanent or removable column strengthenhancing mandrels, two or more lumen such as to permit drug or irrigantinfusion or radiation delivery or to supply inflation media to aninflatable balloon, or to permit aspiration or other removal ofthrombus, or combinations of these features, as will be readily apparentto one of skill in the art in view of the disclosure herein. Inaddition, the present invention will be described primarily in thecontext of restoring flow in the outflow vasculature from the brain,although the devices disclosed herein may be introduced into otherveins, arteries or hollow structures in the body.

The catheter 40 generally comprises an elongate tubular body 42extending between a proximal end 44 and a distal functional end 46. Thelength of the tubular body 42 depends upon the desired application. Forexample, lengths in the area of from about 120 cm to about 140 cm ormore are typical to reach the jugular veins via femoral access. Adifferent catheter shaft length may be appropriate depending upon thevascular access site, as will be understood in the art.

The proximal end 44 of catheter 40 is additionally provided with ahandle 48 having one or more access ports as is known in the art.Generally, handle 48 is provided with a guidewire port 50 in anover-the-wire construction, and optionally an aspiration or infusionport (not illustrated). The guidewire port 50 may comprise a standardluer connector, and is in communication with a distal guidewire accessport 52 by way of an elongate guidewire lumen 54. Alternatively,aspiration or infusion may be accomplished through the guidewire lumenin an OTW configuration if the guidewire is proximally retractedfollowing placement of the catheter 40.

A rapid exchange configuration may be provided, by eliminating theproximal luer connector at the proximal guidewire port 50, andpositioning the proximal guidewire port 50 along the side wall of thetubular body 42. Generally, the proximal guidewire access port 50 in arapid exchange configuration will be positional within about 20 cm, and,in some embodiments, within about 10 cm from the distal guidewire port52 as is understood in the art. Additional access ports may be providedas needed, depending upon the desired functional capabilities of thecatheter. Handle 48 may be injection molded from any of a variety ofmedical grade plastics, or formed in accordance with other techniquesknown in the art.

Referring to FIG. 3, the catheter 40 comprises an axially moveable outersleeve 56 which is shown in a proximally retracted orientation. Sleeve56 is axially moveably carried by an elongate core 58, which steps downin diameter at a distally facing shoulder 60 to provide an annularrecess 62 for releasably receiving an implant. The distal end of thecore 58 is provided with an atraumatic tip 64, to facilitate innavigation and minimize trauma to the vessel wall. Tip 64 extends fromthe distal guidewire port 52 to a proximal end 66 configured to providea smooth exterior surface when the outer sleeve 56 is in a distalposition to enclose and restrain an implant within the chamber formed byannular recess 62.

The cross-sectional view of FIG. 4 illustrates the outer sleeve 56axially moveably carried by the flexible core 58, and shows a guidewire68 positioned within the central guidewire lumen 54.

Referring back to FIG. 2, handle 48 is additionally provided with acontrol 70, for controlling the axial position of the outer sleeve 56relative to core 58. Control 70 may take any of a variety of formsdepending upon the desired physician interface. In the illustratedembodiment, control comprises an axially moveable slider switch 72 whichis movable along an axial slot 73. Slider switch 72 is mechanicallylinked to the outer sleeve 56 such that proximal retraction of theslider switch 72 produces a proximal movement of the sleeve. Thisexposes the annular recess 62 and allows deployment of a self-expandableimplant restrained therein.

Any of a variety of controls 70 may be utilized, including switches,levers, rotatable knobs, pull/push wires, and others which will beapparent to those of skill in the art in view of the disclosure herein.

Avoiding a tight fit between the guidewire 68 and inside diameter ofguidewire lumen 54 enhances the slideability of the catheter over theguidewire. In ultra small diameter catheter designs, it may be desirableto coat the outside surface of the guidewire 68 and/or the insidesurface of the wall defining lumen 54 with a lubricous coating tominimize friction as the catheter 40 is axially moved with respect tothe guidewire 68. A variety of coatings may be utilized, such asParalene, Teflon, silicone rubber, polyimide-polytetrafluoroethylenecomposite materials or others known in the art and suitable dependingupon the material of the guidewire or inner tubular wall of lumen 54.

In general, the inside diameter of guidewire lumen 54 will be at leastabout 0.003 inches or greater larger than the outside diameter of theintended guidewire. Guidewires having diameters in the range of fromabout 0.009 inches to about 0.016 inches are presently contemplated.

Catheters of the present invention which are adapted for intracranialapplications generally have a total length in the range of from 60 cm to250 cm, usually from about 135 cm to about 175 cm. The length of theproximal segment 33 will typically be from 20 cm to 220 cm, moretypically from 100 cm to about 120 cm.

The catheters of the present invention may be constructed from any of avariety of known biologically compatible polymeric resins havingsuitable characteristics when formed typically by extrusion into thetubular catheter body segments. Exemplary materials include a variety ofmedical grade polyvinyl chloride, polyethers, polyamides, polyethylenes,polyurethanes, copolymers thereof, and the like. Suitable speciesinclude PEBAX, PEEK, and others known in the angioplasty arts. Incertain embodiments, the distal tip 64 may be formed from more elasticmaterials, such as latex rubber, silicone rubber, and blends thereof.

The catheter body 42 may further comprise other components, such asradiopaque fillers; colorants; reinforcing materials; reinforcementlayers, such as braids and helical reinforcement elements; or the like.In particular, a proximal zone on body 42 may be reinforced in order toenhance its column strength and torqueability while preferably limitingits wall thickness and outside diameter.

Radiopaque markers may be provided at least at the proximal and/ordistal ends of the annular recess 62. The implant may comprise aradiopaque material or be provided with markers. Other radiopaquemarkers may be provided elsewhere, such as on the distal end of themovable sleeve 56. One radiopaque marker comprises a metal band which isembedded within the wall of the sleeve 56 or core 58. Suitable markerbands can be produced from a variety of materials, including platinum,gold, and tungsten/rhenium alloy.

The tubular body 42 may be produced in accordance with any of a varietyof known techniques for manufacturing interventional catheter bodies,such as by extrusion of appropriate biocompatible polymeric materials.Alternatively, at least a proximal portion or all of the length oftubular body 16 may comprise a polymeric or metal spring coil, solidwalled hypodermic needle tubing, or braided reinforced wall, as is knownin the microcatheter arts.

In many applications, the tubular body 42 is provided with anapproximately circular cross-sectional configuration having an externaldiameter within the range of from about 0.025 inches to about 0.065inches. Alternatively, a generally oval or triangular cross-sectionalconfiguration can also be used, as well as other noncircularconfigurations, depending upon the method of manufacture, number andarrangement of internal lumens and the intended use.

In a catheter intended for peripheral vascular applications, the body 42may have an outside diameter within the range of from about 0.039 inchesto about 0.065 inches. In coronary vascular applications, the body 42may have an outside diameter within the range of from about 0.025 inchesto about 0.045 inches. Catheters configured to access the externaljugular vein 22 will typically have an outside diameter of no more thanabout 0.045 inches, and as low as about 0.028 inches or about 0.025inches or about 0.022 inches or lower.

Diameters outside of the preferred ranges may also be used, providedthat the functional consequences of the diameter are acceptable for theintended purpose of the catheter. For example, the lower limit of thediameter for any portion of tubular body 42 in a given application willbe a function of the number of fluid or other functional lumen containedin the catheter, together with the collapsed diameter of the implant.

Tubular body 42 must have sufficient structural integrity (e.g., columnstrength or “pushability”) to permit the catheter to be advanced todistal locations without buckling or undesirable bending of the tubularbody. The ability of the body 16 to transmit torque may also bedesirable, such as to avoid kinking upon rotation, to assist insteering. The tubular body 42, may be provided with any of a variety oftorque and/or column strength enhancing structures. For example, axiallyextending stiffening wires, spiral wrapped support layers, braided orwoven reinforcement filaments may be built into or layered on thetubular body 16. See, for example, U.S. Pat. No. 5,891,114 to Chien, etal., the disclosure of which is incorporated in its entirety herein byreference.

Alternatively, any of a variety of the implants disclosed herein can beconfigured for deployment from a balloon catheter. In a most basicembodiment, a balloon expandable stent is provided with a valve andcarried in a collapsed configuration over a deflated balloon to thedeployment site. The balloon is inflated at the deployment site toexpand the stent, leaving the stent and valve construct at thedeployment site following deflation and proximal retraction of theballoon catheter. Many of the dimensions and considerations previouslydiscussed in connection with self-expandable implant deployment systemswill also guide the design of suitable balloon catheter deploymentsystems. Balloon catheters intended for deployment of an implant in theazygos vein may have an inflated balloon diameter within the range ofabout 6 mm to about 8 mm, and an inflated diameter within the range ofabout 8 mm to 16 mm for balloons intended to deploy an implant in thejugular vein.

Certain stenoses in the extracranial venous vasculature require arelatively high inflation pressure in order to recanalize the lumen.Inflation pressures of at least about 18 atmospheres or 20 atmospheresor more are often desirable. As a consequence, deployment of aself-expanding implant preferably will be preceded by a balloondilatation. The valves associated with balloon expandable implants,particularly if a tissue valve is utilized, may or may not tolerate thecompression resulting from high inflation pressures. Thus, dependingupon the valve design, either a pre-implantation balloon dilatation maybe preferred, or the dilatation can be accomplished simultaneously withexpansion of the implant at the deployment site.

Resistant stenoses may alternatively be dilated using a cutting balloon.Cutting balloons are known in the percutaneous transluminal coronaryangioplasty arts, and include one or more axially elongate incisingelements mounted on the exterior of the inflatable balloon. One exampleof a cutting balloon may be seen in U.S. Pat. No. 7,799,043 to O'Brienet al. (Boston Scientific) the disclosure of which is herebyincorporated in its entirety herein by reference.

As a further alternative, the implant may be a two or more partconstruct which is assembled in situ at the deployment site. Forexample, a support structure such as a stent can be carried by a balloonto the deployment site, and expanded under high pressure to generatesufficient radial force to dilate both the stent and the lesionutilizing a first procedure catheter. A second procedure catheter maythereafter be introduced and positioned within the support structure, todeploy the valve. The valve deployment may either be accomplished by aballoon catheter, which may have a lower inflation pressure than thefirst procedure catheter, or in a self-expanding mode. The valve iscoupled to the support structure, to produce the final construct.

Certain exemplary valve and support structure constructs will bedescribed below. The present invention contemplates the use of any ofthe valve structures described below with any of the support structuresdescribed below, and not merely the specific examples given. In general,the implant can take any of variety of forms including a tubularscaffold without a valve, or a tubular scaffold with a valve on the samedevice. Alternatively, the tubular scaffold and the valve may beseparately implanted and connected or associated in situ. Any of thevalves disclosed herein may be alternatively be configured for anchoringto the vessel wall or within the vessel using a structure other than atubular scaffold. As used herein, terms such as scaffold or supportstructure may include a form of a stent, but also include intravascularsupport structures which might not be considered a stent. The supportstructures can be balloon expandable, or self-expandable, or notexpandable at all, such as in the case of certain hooks or barbs,depending upon the desired configuration.

Referring to FIGS. 5A and 5B, there is illustrated one exemplary valvein accordance with the present invention. As illustrated therein, thetubular wall 70 of the vein defines a blood flow lumen 72. An implant 74is positioned within the lumen 72. The implant comprises a supportstructure 76 which supports at least one occluder 78.

In the illustrated embodiment, the occluder is in the form of acollapsible cone or wind sock extending from an apex 80 at an upstreamend to a downstream opening 82 having a fully opened diameter at leastas great as the inside diameter of the lumen. The occluder 78 is securedat apex 80 and at one or more points along its length on a first,fixation side of the occluder to the support structure 76. A second,opposing dynamic side of the implant 74 is moveable between a radiallyexpanded (occlusive) configuration as illustrated in FIG. 5A and aradially compressed configuration as illustrated in FIG. 5B.

As implanted in a vessel, retrograde flow 84 has a tendency to enter theopen end of the occluder in a manner like a wind sock and advance thedynamic side across the lumen to occlude further retrograde flow.Referring to FIG. 5B, antegrade flow (e.g. towards the heart) has theeffect of collapsing the occluder 78 by forcing the dynamic side againstthe wall of the lumen and permitting forward flow.

Although illustrated as having only a single occluder 78, two or threeor four or more inflatable and collapsible occluder elements maycooperate with each other to achieve the same functionality, in whichthe valve is either opened or closed in response to the direction ofblood flow.

The occluder 78 may comprise any of a variety of materials, preferablyin the form of a thin blood impermeable membrane. Preferably, themembrane is highly compliant and responsive to subtle changes in bloodflow. The thickness of the membrane can be optimized by those of skillin the art in view of the composition of the membrane. Presentlycontemplated ePTFE membranes will typically have a thickness of no morethan about 0.01 inches and, in some embodiments, no more than about0.005 inches or 0.001 inches or less. Ultrathin membranes of any of avariety of polymers utilized in the catheter arts may also be used, suchas nylon, polyethylene terephthalate, PEEK, various densities ofpolyethylene and others known in the art. Alternatively, ultrathin metalmesh membrane or porous metal membranes may be utilized, provided thatthey demonstrate the desired physical properties.

Preferably, the material of the membrane as well as the supportstructure will be antithrombogenic or at least resist thrombus formationeither inherently, or through the provision of an antithromboticcoating.

In the ultrathin membrane embodiments, one or two or more axiallyextending struts may desirable be incorporated within or attached to theoccluder 78, to improve the structural integrity of the membrane in theenvironment of high velocity blood flow. Depending upon the desiredperformance, the membrane may either be completely impermeable to bloodflow, or may be provided with a level of porosity that permits a smallamount of retrograde blood flow. Pore sizes of no more than about 100μand in some embodiments no more than about 50μ or 20μ may be used.

The support structure 76 may comprise any of a variety of balloonexpandable or self-expandable stents, or other support structure that issufficient to retain the occluder 78 at the desired deployment site andresist migration under the force of blood flow. Thus, for example, theapex 80 may be secured directly to the vessel wall, using any of avariety of attachment techniques such as clips, sutures, staples, orother barb structures which extend into and optionally through the wall70.

In the illustrated embodiment, the support structure 76 comprises atleast one self-expanding tubular support in the form of a stent 86. Thestent comprises a plurality of struts 88 extending in a zig-zag fashionhaving a plurality of alternating proximal apexes 90 and distal apexes92, a structure some times referred to as a “Z” stent. The struts 88 maycomprise any of a variety of materials having suitable properties, suchas Nitinol, stainless steel, Elgiloy or others known in the art.

In the illustrated embodiment, a first tubular support 86 is spacedaxially apart from a second tubular support 94 and connected by anaxially extending strut 96. The axially extending strut 96 serves toboth maintain the spatial relationship of the first and second tubularsupports, as well as provide an attachment structure for the fixationside of the conical occluder. The occluder may be attached to thesupport structure at the point of manufacture, and introduced into thevessel as a single unit. Alternatively, the support structure may bedeployed in a first step, and the occluder carried into position andattached to the support structure in situ in a second step.

Referring to FIGS. 6A and 6B, there is illustrated a modification of thewind sock valve discussed above. In this illustration, the occluder 78is mounted “off board” from the support structure 76, and securedagainst axial relative movement by a plurality of struts 98. In thisconstruction, the occluder 78 is preferably provided with at least oneor two or three or more longitudinal extending ribs 100, in the natureof a sail batton. The battons allow the occluder 78 to reciprocatebetween the closed configuration of FIG. 6A and open configuration ofFIG. 6B, in response to blood flow, without axial collapse or prolapseof the conical occluder membrane. The battons may be secured to an inneror outer surface of the membrane forming the occluder, or may beentrapped between an inner membrane and an outer membrane which arebonded together to form the finished occluder.

Referring to FIG. 7A, there is illustrated a side elevational view of analternate implant in accordance with the present invention. In theillustrated embodiment, a first tubular support 86 and a second tubularsupport 94 are connected by a backstop 102. A single tubular support mayalternatively be used, which may extend approximately equal to the axiallength of the backstop 102, or less than or greater than the axiallength of the backstop 102.

Referring to FIG. 7B, there is illustrated a top plan view of theimplant of FIG. 7A, illustrating the backstop as at least one andpreferably a plurality of struts 104 which extend at a diagonal acrossthe blood flow lumen to permit blood flow therethrough. As illustratedin FIG. 7C, the backstop 102 serves to support an occluder membrane 106.The occluder membrane 106 is secured at least at an attachment point 108with respect to the tubular support. As illustrated in FIG. 7C,retrograde blood flow in the direction 110 pins the occluder membrane106 against the backstop 102, thereby inhibiting further retrogradeblood flow. As illustrated in FIG. 7D, antegrade blood flow in thedirection 112 flows through the struts 104 of the backstop 102, andpushes the occluder 106 against the wall of the lumen, permittingforward blood drainage towards the heart.

In one implementation of the invention, the occluder 106 comprises asubstantially oval shaped profile, such that it approximately conformsto the wall of the lumen when in the occlusive orientation illustratedin FIG. 7C. See FIG. 7E. The occluder 106 may be provided with one ormore attachment points 108 for flexible or pivotable attachment to thesupport structure. In the illustrated implementation, attachmentstructure 108 may comprise an eyelet on one end of an elongate wire orpolymeric batton 110. At least one, and often at least two or three ormore battons 110 are provided, spaced apart and generally parallel tothe major axis of the oval. In this manner, the structural integrity ofthe occluder 106 may be maintained, while at the same time preservingflexibility of the occluder 106 to bend into an arc about an axis whichis parallel to its longitudinal axis, such that it may conform to theinner surface of the vessel wall when in the open configurationillustrated schematically in FIG. 7D. As has been previously discussed,the occluder 106 may comprise any of a variety of thin film membranes,such as ePTFE, or tissue such as pericardium may alternatively be used.In one embodiment, the battons 110 comprise elongate polymeric elementssandwiched between a first and second layer of ePTFE. The facing ePTFEsurfaces may be provided with a bonding layer such as FEP, so that thecomposite stack may be heated under pressure to produce the finishedoccluder 106.

Any of a variety of alternative valve construction may be utilized,depending upon the desired performance result. For example, referring toFIG. 8, there is illustrated a schematic view of a simple bi-leafletduck bill valve 114. A support structure such as a balloon expandable orself-expandable stent 112 is illustrated positioned within a vessel 70.

In the illustrated embodiment, the valve 114 comprises a first leaflet116 coaptively engaged with a second leaflet 118 to enable flow in asingle direction. Single leaflet, bi-leaflet, tri-leaflet or othervalves may be utilized, although bi-leaflet or tri-leaflet may bepreferred. Suitable valves may be harvested from porcine, bovine, canineor other animal sources known in the art, or may be constructed such asfrom bovine, porcine or human tissue. The harvesting, treatment and use,for example, of pericardium is well understood in the prosthetic heartvalve arts, and not disclosed in detail herein. Alternatively,autologous valves such as venous valves harvested from the peripheralvasculature of a patient may be prepared and deployed in accordance withthe present invention.

The support structure for the venous valves in accordance with thepresent invention function to support the valve in an operativeorientation within the vein, and resist migration away from thedeployment site. A stent or stent like tubular structure is oneconvenient form of a support, and provides the basis for much of thediscussion herein. However, structures which do not resemble aconventional stent may alternatively be used.

For example, referring to FIG. 9A there is illustrated a valve 114having an annulus 120 connected to a support structure 122. Supportstructure 122 comprises an elongate flexible element such as a wire,which extends in a helical loop in contact with the vascular wall. Oneor two or more loops may extend in a downstream flow direction from theannulus 120 and or one or two or more loops may extend in an upstreamflow direction from the annulus 120. The annulus 120 may be supported bya loop of the support structure 122, and leaflets 116 and 118 may besecured such as by suturing to the annulus 120. The spiral or pigtailloop anchors may be formed from any of a variety of materials includingmetal wire such as Nitinol, which enables collapse to a relatively lowcrossing profile during deployment and self-expansion to fit within thevessel.

A variation is illustrated in FIG. 9B, in which a pigtail or haptic likeanchor 124 is provided upstream of the valve 114 and a second pigtailanchor 126 is provided downstream of the valve 114. Each anchor extendsin a spiral through no more than about one or two complete revolutionsalong the vessel wall. In any of the supports disclosed herein, two orthree or more axially extending commissural supports may be added asneeded, and secured relative to annulus 120, such as three commissuralsupports if a tri-leaflet tissue valve is used.

Referring to FIG. 9C, there is schematically illustrated a stentlessvalve system, in which the annulus 120 or a structure secured to theannulus 120 is directly attached to the vessel wall. Attachment may beaccomplished utilizing any of a variety of tissue penetratingstructures, such as sutures, clips or barbs, configured for deploymentfrom a catheter. In the illustrated embodiment, at least a first tissuepenetrating anchor 128 extends from the annulus 120 into the vesselwall. The tissue penetrating anchor may be provided with a transverseelement for placement against the extravascular surface, such as a “T”tag 132 as is known in the art. At least a second tissue penetratinganchor 130, which may additionally be provided with a transverse distalelement may additionally be provided. At least two or four or six ormore tissue penetrating anchors may be utilized for each valve,depending upon the desired performance.

In any of the stent or other support structure systems disclosed herein,any of a variety of features may be added to inhibit migration withinthe vessel. For example, referring to FIG. 10A, a valve 114 isschematically illustrated as a bi-leaflet valve. The valve 114 issupported by a support structure 132, such as a tubular stent. Thesupport structure 132 is deployed within a vessel wall 134. A pluralityof tissue engaging structures such as barbs 136 extend from the support132 into the wall of the vessel. Barbs 136 may extend transversely tothe longitudinal axis of the vessel, or may be inclined in an antegradeor a retrograde flow direction.

Referring to FIG. 10B, an implant is illustrated in which a firstportion 138 of the support is positioned on a first side of a nativevalve 140 and a second portion 142 of the support is positioned on asecond side of the native valve 140. A prosthetic valve (notillustrated) may be carried by the support construct at any point alongthe length of the implant. At least one, and preferably two, or three ormore axially extending elements 144 link the first portion 138 and thesecond portion 142 such that the construct spans the native valve, whichserves as an anchor against axial migration. Tissue penetrating elementsor other surface structures may additionally be utilized, as desired.

The anchor system may also be customized to unique anatomicalenvironments. For example, FIG. 10C illustrates an embodiment which maybe useful in anatomy such as the left internal jugular or externaljugular, which may join the subclavian vein at a nearly perpendicularangle. A tubular support 146 may be positioned in the left internaljugular, having at least one valve thereon to replace native valvefunction. The support 146 is provided with a base 150 which establishesa footprint against the wall of the subclavian vein opposing the ostiumto the left internal jugular. The base 150 may be spaced apart from thesupport 146, such as by one or two or four or more struts 148. Struts148 are configured to resist downstream migration of the support 146,yet permit transverse venous flow from the subclavian into the leftinnominate vein.

Referring to FIG. 10D, the support structure may also cooperate with oneor more extra vascular structures, to resist migration within the vein.The valve 114 in FIG. 10D is provided with an annular structure 152 suchas the valve annulus or other radially outwardly projecting supportstructure attached to the annulus, having a first, deployed outsidediameter measured transverse to blood flow. The vein 153 extends throughan anatomical structure such as a foramen 155 in the base of the skull157, having a second diameter which is smaller than the first diameter.This enables the valve to hang from the anatomical structure withoutmigration.

Migration may also be inhibited through the use of one or more extravascular structures, which provide an interference fit through thevenous wall with a component on the valve to inhibit migration.Referring to FIG. 10E, an extra vascular structure such as an annularcuff 156 establishes an inside diameter within the vein, which cannot beexceeded under normal environmental conditions. Extra vascular cuff 156may comprise any of a variety of structures, such as a metal orpolymeric ring, mesh, suture loop, or other structure, most readilyimplanted via direct surgical access.

A radially outwardly extending element such as a projection, flange orannulus 158 is provided on the implant 160. The outside diameter of theannulus 158 plus the wall thickness of the vein 153 exceeds the insidediameter of the extra vascular cuff 156, thereby inhibiting downstreammigration of the valve.

In accordance with the method of the present invention, a patient isidentified having an obstruction in the venous outflow track from thebrain. The obstruction may be identified using doppler ultrasound inaccordance with techniques well understood in the art. The dopplerultrasound may be accomplished on patients with a clinical diagnosis oftransient global amnesia, multiple sclerosis, or any of a variety ofsymptoms associated with multiple sclerosis, such as paresthesias,numbness, limb weakness, double vision, visual loss, complete localmotor dependency, urine incontinence and cognitive decline. Dopplerultrasound may be performed on patients diagnosed with multiplesclerosis, in any of the three main clinical courses of relapsingremitting, secondary progressive, and primary progressive. Evaluationmay include sonographic (extracranial echo color-doppler andtranscranial color-doppler ultrasound) evaluation.

Once a stenotic lesion as been identified, percutaneous access to thevenous vasculature may be achieved for example at the femoral vein, anda balloon dilatation catheter may be advanced over or along a guidewireto position the balloon within the lesion. The lesion is thereafterdilated, the balloon deflated and removed in accordance with techniqueswell understood in the art.

In certain implementations of the invention, dilation is accompanied byplacement of an intravascular stent, without implantation of a valve.

In an alternative implementation of the invention, the dilation isfollowed by placement of a valve, carried by a support structure such asa stent. In general, stenotic lesions which are spaced apart from thenative valves, may be dilated and supported with an intravascular stentin the absence of implantation of a valve. However, lesions involving avalve, or other valvular dysfunction may suggest the desirability ofimplantation of one or more valves of the type disclosed previouslyherein.

In one example, one or two valves in the left internal jugular havebecome undesirably resistive to forward blood flow. The valve isaccessed via conventional techniques, and a valvuloplasty isaccomplished by dilation of a balloon or other expansion structurewithin the valve to restore patency to the lumen. The valvuloplastycatheter may comprise a bare balloon, or a balloon which carries anintravascular support such as a stent. A valve may be associated withthe intravascular support.

Alternatively, the valvuloplasty balloon may be utilized to deploy astent or other support structure in the vicinity of the dilated valvesimultaneously with valve dilatation. The valvuloplasty balloon catheteris removed from the patient, and a valve deployment catheter isthereafter positioned within the deployed support. A valve carried bythe valve deployment catheter is coupled to the support, and the valvedelivery catheter is proximally retracted from the patient leaving thevalve coupled to the support at the treatment site.

It is believed that the implanted valve need not necessarily reside atthe same location as the native valve. Thus, a valve and valve supportstructure may be deployed within the vasculature, spaced apart from thedilated valve. Balloon dilatation of valves in the right internaljugular, for example, may therefore be followed by placement of a valvein either the right internal jugular or the right innominate vein.Similarly, balloon dilation of one or more valves in the left internaljugular may be followed by implantation of one or more valves in theleft internal jugular or the left innominate vein. As a furtheralternative, balloon dilation, with or without stenting, of any of avariety of valves in the venous outflow track from the brain may befollowed by positioning of a valve in the superior vena cava. Forexample, referring to FIG. 11 there is disclosed a valve carried by asupport structure such as a stent and positioned within the superiorvena cava. As illustrated, the valve is positioned in between the ostiumto the azygos vein and the heart. The valve may alternatively bepositioned between the azygos vein and the bifurcation of the right andleft innominate vein.

In addition to any of the foregoing, it may be desirable to implant afilter in the flow path between the treatment site and the heart, if arisk of embolization to the heart is a concern. Thus, referring to FIG.12, there is illustrated a vena cava filter positioned within thesuperior vena cava. Any of a variety of filters presently configured fordeployment within the inferior vena cava may be adapted for use in thisenvironment, and may be any of a variety of self-expandable frame orframe and mesh structures.

Either as an alternative to or in addition to any of the foregoingpercutaneous or minimally invasive procedures, methods and devices inaccordance with the present invention can also be optimized for surgicalintervention. Thus, referring to FIG. 13, there is illustrated anextravascular valved venous graft 200. The venous graft 200 has beenanastomosed to the native vasculature to place a superior opening 202 influid communication with an inferior opening 204 to bypass one or bothof venous valves 32 and 34. In the illustrated implementation, valve 32and 34 are both partially or fully obstructed by thrombus or othercondition 206.

The extravascular valved venous graft 200 comprises an elongate flexibletubular body 208 extending between a superior end 210 and an inferiorend 212. Superior end 210 is provided with an end to side anastomosis214 to the left internal jugular vein, utilizing sutures 216 or otherclips or attachment techniques known in the art. Inferior end 212 oftubular body 208 is connected via anastomosis 218 at the inferioropening 204 to the left innominate vein 26. Tubular body 208 thusprovides a bypass conduit for cerebral venous drainage, avoiding theobstruction 206.

Tubular body 208 may be provided with at least a first valve 220, and,optionally, at least a second valve 222. Any of a variety of valvesstructures such as those disclosed elsewhere herein may be utilized.Tubular body 208 may comprise any of a variety of materials suitable foruse in vascular grafts, such as ePTFE, Dacron, or other fabric orextrudable polymers. The tubular body 208 may be supported along atleast a portion or the entire length thereof to maintain patency of thegraft 200. Any of a variety of support structures may be utilized, suchas an end-to-end construct of Z stent structures as has been disclosedelsewhere herein. Alternatively, since the endovascular valved venousgraft 200 is intended for surgical implantation, the ability to collapseand expand may not be necessary. Thus, any of a variety of reinforcingstructures such as a plurality of axially spaced apart annular rings orhoops, or a helical wire or polymeric filament support may be attachedto the interior surface or the exterior surface of the graft 200, orentrapped between an inner tubular layer and an outer tubular layer.Techniques for surgical implantation and anastomosis of bypass graftsare well understood in the coronary and peripheral vasculature, and willnot be detailed further herein.

As an alternative to extravascular bypass as illustrated in FIG. 13, anoccluded segment of vein can be severed, and completely removed from thevasculature. Depending upon the length of the occlusion, the free endsof the remaining vasculature may be brought together and anastomosed toprovide fluid flow with or without insertion of a prosthetic valve.Alternatively, as illustrated in FIG. 14, a valved vascular graft 230may be used to replace the removed segment of vein. The graft 230comprises an elongate flexible tubular body 232 having at least onevalve 240 illustrated as replacing a segment of the left internaljugular from which a section of vein having one or more vein valves hasbeen removed. Tubular body 232 is connected via a superior anastomosis234 and an inferior anastomosis 236 using sutures 238 or otherattachment techniques known in the art. The graft 230 may be supportedalong a portion or all of its length, and may otherwise be provided withany of the features described previously in connection withextravascular valved venous graft 200.

As an alternative to the prosthetic grafts described above, nativetissue (typically autologous) can be harvested, prepared and implantedin accordance with the methods of the present invention. Thus, either ofthe valved grafts 200 (of FIG. 13) or 230 (of FIG. 14) can be formedfrom a section of a vein such as the saphenous vein, including at leastone valve, which can be harvested in accordance with known techniquesand surgically implanted in accordance with the methods describedpreviously herein.

Hybrid procedures may also be utilized, such as balloon valvuloplasty ofa valve in the venous outflow track from the brain, followed by surgicalaccess to implant a prosthetic valve. Any of a variety of valveconfigurations may be utilized for surgical implantation, as will beappreciated by those of skill in the art. For example, a valve adaptedfor surgical implantation is illustrated in FIGS. 15A & 15B. Valve 114comprises a first leaflet 116, a second leaflet 117 and a third leaflet118 although bi-leaflet valves may alternatively be used. The leafletsare supported by an annulus 120, as is understood in the art. Annulus120 may comprise a native tissue annulus, in a valve such as a porcineor bovine valve. A tissue annulus 120 may be secured directly to thevein, such as by sutures.

Alternatively, in a prosthetic valve such as one in which the leafletscomprise a polymeric membrane or tissue such as pericardium, the annulus120 may comprise a biocompatible metal or polymer. In this instance, afabric coating 121 such as a Dacron or ePTFE sleeve may be provided overthe annulus 120, to form a sewing ring such that sutures can be stitchedthrough the fabric 121 into adjacent venous tissue.

Alternatively, the valve 114 may be supported within a length of tubulargraft 250, as schematically illustrated in FIG. 16. Valve 114 may besutured or otherwise secured to the section of graft 250, which providesa convenient attachment structure for attachment to the vein. Graft 250may comprise any of a variety of materials discussed previously herein,such as ePTFE or Dacron. The annulus 120 of valve 114 may be secureddirectly to the graft 250, such as by sutures, adhesives, clips or otherattachment technique. Alternatively, an optional stent 114 may beprovided, to secure the valve and/or support the graft 250 and maintainpatency in the vicinity of the valves. First end 252 and second end 254of graft 250 may be attached directly to the vein. The axial length ofgraft 250 will typically be at least about 1 cm or 2 cm, and often atleast about 5 cm. Graft 250 may be provided in lengths of at least about10 cm or 20 cm, and the implantation step may include the step ofcutting the graft 250 to a desired length prior to surgically attachingthe graft 250 to the native vasculature. At least one or two or three orfour or more valves 114 may be provided within graft 250.

In accordance with a further aspect of the present invention, there isprovided a formed in situ valve. Formed in situ valves may beconstructed either translumenally, surgically or a combination of both.

Referring to FIGS. 17-19B, formed in situ valve 258 is formed in asection of vessel 260. Vessel 260 may be a segment of vein, such as anyof the veins described previously herein. Alternatively, vessel 260 maycomprise any of a variety of other tubular organs or vessels such asarteries.

Vessel segment 260 defines a central flow lumen 261 which permits bloodflow in a downstream flow direction 263. Flow thus extends from anupstream side 262 to a downstream side 264 of the valve.

The valve is formed by creating an incision 266 having a generally Ushape, such that a first end 267 and second end 269 of incision 266 areoriented in a relative upstream direction, and a free end 272 isoriented in a downstream direction. Incision 266 thus creates a flap 268which remains connected to the vessel 260 via a hinge 270. Thisconstruction enables the flap 268 to pivot about the vicinity of thehinge 270 and close the central lumen 261 as illustrated in FIG. 17B.Flap 268 may be most conveniently formed through surgical procedures,although transluminal devices may be devised to construct the flap 268.

Due to the thin nature of the venous wall, a flap 268 in the presence ofreverse direction blood flow may well be carried in an upstreamdirection beyond the hinge 270 and not provide any valving function.Thus, a backstop 274 which comprises a limit surface such as a pluralityof spaced apart struts 276 may be positioned within the vessel, to limitupstream movement of the flap 268 beyond a closed orientation. Backstop274 may be integrally formed with or attached to a support 278 which maycomprise any of a variety of balloon expandable stents, self-expandablestents or other attachment structures such as those disclosed elsewhereherein. Backstop 274 may be introduced into the vessel either via theincision 266 in a surgical procedure, or translumenally via a remotevascular access site. As illustrated in FIG. 18B, backstop 274 providesa surface which resides at an angle with respect to the longitudinalaxis of the vessel 260. The angle may be anywhere within the range fromabout 90° to about 35° or 40°, depending upon the diameter of thevessel, length of the flap 268 and desired performance characteristics.

Since the flap 268 functions as the occluder in the formed in situ valve258, when the flap 268 is in the “closed” orientation as in FIG. 17B,venous flow would escape via incision 266. Thus, referring to FIG. 19A,a patch 280 is positioned over the incision 266 to enclose the lumen261, and permit flap 268 to reciprocate between an occlusive or closedorientation as in FIG. 19A, and an open or forward flow orientation asillustrated in FIG. 19B. The patch may comprise any of a variety ofmaterials, such as autologous tissue (e.g. pericardium), or any of avariety of fabrics or mesh such as Dacron or ePTFE. Patch 280 may besutured to the vein wall, attached using clips, adhesives, extravascularannular cuffs or other structures for surrounding the patch and thevein.

Any of the valves or valve supports deployed in accordance with thepresent invention may be coated with or otherwise carry a drug to beeluted over time at the deployment site. Any of a variety oftherapeutically useful agents may be used, including but not limited to,for example, agents for inhibiting restenosis, inhibiting plateletaggregation, or encouraging endothelialization. Some of the suitableagents may include smooth muscle cell proliferation inhibitors such asrapamycin, angiopeptin, and monoclonal antibodies capable of blockingsmooth muscle cell proliferation; anti-inflammatory agents such asdexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, acetyl salicylic acid, and mesalamine, lipoxygenaseinhibitors; calcium entry blockers such as verapamil, diltiazem andnifedipine; antineoplastic/antiproliferative/anti-mitotic agents such aspaclitaxel, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin,cyclosporine, cisplatin, vinblastine, vincristine, colchicine,epothilones, endostatin, angiostatin, Squalamine, and thymidine kinaseinhibitors; L-arginine; antimicrobials such astriclosan, cephalosporins,aminoglycosides, and nitorfuirantoin; anesthetic agents such aslidocaine, bupivacaine, and ropivacaine; nitric oxide (NO) donors suchas lisidomine, molsidomine, NO-protein adducts, NO-polysaccharideadducts, polymeric or oligomeric NO adducts or chemical complexes;anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGDpeptide-containing compound, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin antibodies, anti-platelet receptorantibodies, enoxaparin, hirudin, Warafin sodium, Dicumarol, aspirin,prostaglandin inhibitors, platelet inhibitors and tick antiplateletfactors; interleukins, interferons, and free radical scavengers;vascular cell growth promoters such as growth factors, growth factorreceptor antagonists, transcriptional activators, and translationalpromotors; vascular cell growth inhibitors such as growth factorinhibitors (e.g., PDGF inhibitor—Trapidil), growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; Tyrosine kinase inhibitors, chymase inhibitors, e.g.,Tranilast, ACE inhibitors, e.g., Enalapril, MMP inhibitors, (e.g.,Ilomastat, Metastat), GP IIb/IIIa inhibitors (e.g., Intergrilin,abciximab), seratonin antagnonist, and 5-HT uptake inhibitors;cholesterol-lowering agents; vasodilating agents; and agents whichinterfere with endogeneus vascoactive mechanisms. Polynucleotidesequences may also function as anti-restenosis agents, such as p15, p16,p18, p19, p21, p2′7, p53, p5′7, Rb, nFkB and E2F decoys, thymidinekinase (“TK”) and combinations thereof and other agents useful forinterfering with cell proliferation. The selection of an active agentcan be made taking into account the desired clinical result and thenature of a particular patient's condition and contraindications. Withor without the inclusion of a drug, certain of the valve supportsdisclosed herein can be made from a bioabsorbable material. Variouspolymeric carriers, binding systems or other coatings to permitcontrolled release of active agent from the valve or support or itscoating are well known in the coronary stent arts and not reproducedherein.

Additional treatment systems and methods of use for application inpatients suffering from Multiple Sclerosis caused by insufficient venouscapacity are described below. This treatment is particularly challengingdue to the large size and compliance of veins and the resulting in thepotential stent migration. Furthermore, some lesions within the venousvasculature can be very fibrotic and difficult to open with standard PTAballoons. More aggressive dilatation devices such as the cutting balloonfrom Boston Scientific, Inc. may have application with the fibroticlesion, but are potentially dangerous to adjacent areas of healthyvessel.

FIGS. 20A-20C show a dilatation device suitable for treatment of theselesions. FIG. 20A shows the device in a first, deflated conditionemployed when the device is being moved and positioned within thevasculature. FIG. 20B shows the device in its inflated conditionemployed when the lesion is being expanded. The device is constructed ofan elongated shaft 300 having a lumen designated to allow a guidewire302 to pass through. Mounted on the very distal end of the catheter is afirst balloon 304 that is designated to be compliant and inflate at lowpressures (i.e. less than 2 ATM). A second compliant balloon 306 ismounted proximally to the first balloon, and is also constructed to becompliant and inflate at similar pressures to the first balloon. A thirdballoon 308 is mounted between the first and second balloons, and isconstructed to be non-compliant or semi-compliant that is capable ofinflating to high pressures (i.e. 14-30 ATM). Optionally, the thirdballoon may have projecting structures 310 overlying it, or attached toits surface to act as stress-concentrators to allow the cutting ortearing of tissue in an predictable way during balloon inflation. Thethree balloons may communicate to a proximal hub or handle (not shown)independently for the purpose of inflation. Alternatively, one or moreof the balloons may share an inflation lumen.

FIGS. 21A-21D show an alternative embodiment of the present device thathas an adaptable second balloon length to match the lesion beingtreated. As shown in FIG. 31A, the device is composed of a firstelongated shaft 300 having a first complaint balloon 304 and anon-compliant or semi-compliant balloon 308. These balloons communicateto a hub or handle via one or more inflation lumens contained within thefirst elongated shaft 300. As seen in FIG. 21B, the device furtherincludes a second elongated shaft 312 upon which a second compliantballoon 306 is mounted. This second balloon communicates to the hub orhandle via an inflation lumen contained within the second elongatedshaft 312. As seen in FIG. 21C, the first shaft 300 is telescopicallyarranged within a lumen of a second shaft 312 so that they are moveableaxially relative to each other. If a relatively long lesion is to betreated, the first and second shafts may be positioned so that the fulllength of the semi-compliant or non-compliant balloon 308 is capable ofexpansion as shown in FIG. 21C. Alternatively, if a shorter lesion isencountered, the second elongated shaft 312 can be distally advanced topartially cover the semi-complaint balloon or non-compliant balloon 308,limiting the length of the balloon that is available for expansion.

FIG. 22 shows a stenosis 314 within a vein 316. The device 318 istracked through the patient's vasculature through a sheath or guidecatheter 320, and positioned so that the distal end of the catheter isnear the stenosis.

Referring to FIG. 23, once the device is positioned within the vein, thefirst compliant balloon 304 is inflated and used to position the devicerelative to the stenosis 314. The balloon provides both visual andtactile feedback to the user regarding its position relative to thestenosis when observed under fluoroscopic guidance.

Referring to FIG. 24, with the first compliant balloon 304 in position,the second compliant balloon 306 is inflated and positioned relative tothe opposite side of the lesion. If both compliant balloons are mountedto the same shaft, the lesion is centered between the two balloons. Ifthe device is constructed as shown in FIG. 21, the first compliantballoon 304 is positioned optimally relative to the first side of thelesion, and then the second compliant balloon 306 is positionedoptimally relative to the second side of the lesion. If the lesion isrelatively short in length, the second shaft 312 may cover a portion ofthe semi-compliant or non-compliant balloon 308. Additionally, ifstress-concentrating projections, e.g., wires, ridges or barbs, as shownin FIG. 20C are present, a portion of them may also be contained withinthe lumen of the second shaft 312.

With the compliant balloons inflated and optimally positioned, thesemi-compliant or non-compliant balloon is inflated to dilate thestenosis. See FIG. 25. If the device is constructed as shown in FIG. 21,only the portion of the balloon that is not covered by the secondelongated shaft will expand. Additionally, if the device hasstress-concentrating structures 310 as seen FIG. 20C, they focus theexpansion pressure and allow disruption of the lesion at lower pressuresand with greater predictability.

Once the lesion has been expanded with the balloon device described inFIGS. 20-25, a stent may be placed to maintain the expanded stenosis.See FIG. 26. The challenge with vessels typically encountered with thepresent procedure is that they are naturally large and compliant. Afterplacement, there is a risk of the stent migrating or embolizing to theheart, which may be life-threatening to the patient. To address thisrisk, the stent is preferably designated to avoid stent migration afterit has been implanted, as has been disclosed previously herein. Thisfigure shows a balloon delivery catheter 322 delivering a balloonexpandable stent 324.

FIG. 27 shows the implanted stent. Typical stents are designed so thatthey maintain a smooth surface both in the expanded and unexpandedconditions. To avoid migration, this stent 324 is not smooth uponexpansion, but instead has a plurality of wall engaging structures suchas crowns 326 that point partially radially outward after the stent hasbeen expanded. These crowns engage in the vessel wall and preventmigration.

FIGS. 28A-28F show a stent design that creates crowns that pointpartially radially outward during stent expansion. FIG. 28A shows atypical stent design in that the stent thickness (t) is greater than itswidth (w). Upon expansion, crowns of this stent will remain smoothbecause it requires less energy to bend the width of the stent than itsthickness as shown in FIGS. 28C & d. Alternatively, 28B shows the designof some of the crowns on the present stent, where the stent thickness(t′) is less than its width (w′) at the crown. Upon expansion, itrequires more energy to bend purely in the stent width, resulting in abuckling effect, where the crown bends out of the surface of the stentand points partially radially outward as shown in FIG. 28F.

FIG. 29 shows a stent pattern that would create a stent that expands asdiscussed in connection with FIG. 27. The stent includes a firstplurality of a first type of crown 328, where its thickness is greaterthan its width, resulting in a smooth crown after expansion. The stentincludes a second plurality of a second type of crown 330, where itsthickness is less than or equal to its width, resulting in a crown thatpoints partially radially outward upon expansion. Both crown types arearranged within the stent pattern strategically, so that the first typeof crown points away from the direction of potential migration, whilethe second type of crown points in the direction of potential migration.Upon expansion, the second type of crowns will expand outward to engagethe vessel wall and prevent stent migration. In an alternativeembodiment, (not shown) the second type of crowns may point away fromthe direction of potential migration as well. In a further alternativeembodiment, not all crowns in a vertical row must be the same, but mayalternate between crown types.

FIG. 30 shows an alternative embodiment of a stent having a plurality oftissue engaging small hooks or barbs on at least one end. These hooksengage the vessel wall and prevent stent migration. The hooks may beintegrated into the pattern of the stent during fabrication, or may beadded on after the stent is fabricated by bonding, welding, solderingand the like.

Although certain preferred embodiments and examples have been describedherein, it will be understood by those skilled in the art that both thedevices and methods of the present invention extend beyond thespecifically disclosed examples to other alternative embodiments and/oruses of the invention and modifications and equivalents thereof. Thus,it is intended that the scope of the present inventive subject matterherein disclosed should not be limited by the particular disclosedembodiments described above, but should be determined by reference tothe following claims.

What is claimed is:
 1. A method of treating cerebrospinal venousinsufficiency, comprising the steps of: identifying a patient having atleast a partial obstruction at a site in the venous outflow track fromthe brain; removing the obstruction; and implanting a valve in fluidcommunication with the site, to permit venous outflow and reduceretrograde pressure.
 2. A method of treating cerebrospinal venousinsufficiency as in claim 1, wherein the removing step comprisesinflating a balloon at the site.
 3. A method of treating cerebrospinalvenous insufficiency as in claim 2, wherein the balloon carries animplant at the time of the inflating step.
 4. A method of treatingcerebrospinal venous insufficiency as in claim 2, further comprisingremoving the balloon and thereafter performing the implanting a valvestep.
 5. A method of treating cerebrospinal venous insufficiency as inclaim 2, wherein the balloon is carried by a catheter introduced intothe vasculature at an access point spaced apart from the site.
 6. Amethod of treating cerebrospinal venous insufficiency as in claim 1,wherein the removing step comprises surgically removing a section ofvein.
 7. A method of treating cerebrospinal venous insufficiency as inclaim 1, wherein the implanting step comprises surgically attaching avalve at the site.
 8. A method of treating cerebrospinal venousinsufficiency as in claim 1, wherein the implanting step comprisesreleasing a valve having a self expandable support at the site.
 9. Amethod of treating cerebrospinal venous insufficiency as in claim 1,wherein the implanting step comprises inflating a balloon within aballoon expandable portion of a valve support at the site.
 10. A methodof treating cerebrospinal venous insufficiency as in claim 7, whereinthe implanting step comprises implanting a tubular graft having a valvemounted therein.
 11. A method of treating cerebrospinal venousinsufficiency as in claim 7, wherein the implanting step comprisesattaching a first end of the graft at a first anastomosis to the leftinternal jugular vein and attaching a second end of the graft at asecond anastomosis to the left innominate vein.
 12. A method of treatingcerebrospinal venous insufficiency as in claim 1, wherein the valve isimplanted in the left internal jugular vein.
 13. A method of treatingcerebrospinal venous insufficiency as in claim 1, wherein the valve isimplanted in the right internal jugular vein.
 14. A method of treatingcerebrospinal venous insufficiency as in claim 1, wherein the valve isimplanted in the azygos vein.
 15. A method of treating cerebrospinalvenous insufficiency as in claim 1, wherein the valve is implanted inthe superior vena cava.
 16. A method of treating cerebrospinal venousinsufficiency as in claim 10, wherein the graft comprises a tubularePTFE wall.
 17. A method of treating cerebrospinal venous insufficiencyas in claim 10, wherein the graft comprises a section of saphenous vein.18. A cerebrospinal venous insufficiency catheter, comprising: a firstelongate, tubular shaft, having an inflation lumen extendingtherethrough; a first balloon carried by the shaft; a second elongate,tubular shaft, having a central lumen, and axially movably carried bythe first shaft, the central lumen having a distal opening; wherein thedistal opening is axially movably positionable between a first positionin which the first balloon is at least partially within the centrallumen, and a second position in which the first balloon is fully exposedbeyond the distal opening.
 19. A cerebrospinal venous insufficiencycatheter as in claim 18, further comprising a second balloon carried bythe first shaft.
 20. A cerebrospinal venous insufficiency catheter as inclaim 18, further comprising a third balloon carried by the secondshaft.
 21. An implant, for positioning in the neurovascular venousoutflow tract, comprising: a radially expandable frame, for engaging thewall of a vein; the frame having a flowpath therethrough; an occludersupport within the frame, extending across the flow path at an inclinedangle relative to the central axis of blood flow; and a thin filmoccluder, movable between a first position spaced apart from theoccluder support sufficient to permit flow through the flow path in afirst direction, and a second position in contact with the support suchthat it inhibits flow through the flow path in a second direction. 22.An implant as in claim 21, further comprising at least one anchor on theframe for engaging the wall of the vein.